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. 2020 Nov 9;12(1):1-13.
doi: 10.1080/19490976.2020.1849998.

From correlation to causality: the case of Subdoligranulum

Matthias Van Hul  1 , Tiphaine Le Roy  1 , Edi Prifti  2   3 , Maria Carlota Dao  3 , Adrien Paquot  4 , Jean-Daniel Zucker  2   3 , Nathalie M Delzenne  1 , Giulio Muccioli  4 , Karine Clément  3   5 , Patrice D Cani  1
Affiliations

From correlation to causality: the case of Subdoligranulum

Matthias Van Hul et al. Gut Microbes. .

Abstract

Gut microbes are considered as major factors contributing to human health. Nowadays, the vast majority of the data available in the literature are mostly exhibiting negative or positive correlations between specific bacteria and metabolic parameters. From these observations, putative detrimental or beneficial effects are then inferred. Akkermansia muciniphila is one of the unique examples for which the correlations with health benefits have been causally validated in vivo in rodents and humans. In this study, based on available metagenomic data in overweight/obese population and clinical variables that we obtained from two cohorts of individuals (n = 108) we identified several metagenomic species (MGS) strongly associated with A. muciniphila with one standing out: Subdoligranulum. By analyzing both qPCR and shotgun metagenomic data, we discovered that the abundance of Subdoligranulum was correlated positively with microbial richness and HDL-cholesterol levels and negatively correlated with fat mass, adipocyte diameter, insulin resistance, levels of leptin, insulin, CRP, and IL6 in humans. Therefore, to further explore whether these strong correlations could be translated into causation, we investigated the effects of the unique cultivated strain of Subdoligranulum (Subdoligranulum variabile DSM 15176 T) in obese and diabetic mice as a proof-of-concept. Strikingly, there were no significant difference in any of the hallmarks of obesity and diabetes measured (e.g., body weight gain, fat mass gain, glucose tolerance, liver weight, plasma lipids) at the end of the 8 weeks of treatment. Therefore, the absence of effect following the supplementation with S. variabile indicates that increasing the intestinal abundance of this bacterium is not translated into beneficial effects in mice. In conclusion, we demonstrated that despite the fact that numerous strong correlations exist between a given bacteria and health, proof-of-concept experiments are required to be further validated or not in vivo. Hence, an urgent need for causality studies is warranted to move from human observations to preclinical validations.

Keywords: Akkermansia muciniphila; Subdoligranulum; subdoligranulum variabile; high-fat diet; human cohort; mice; obesity.

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Figures

Figure 1.
Figure 1.
Subdoligranulum is associated with Akkermansia muciniphila and correlates positively with a healthy metabolic status
Figure 2.
Figure 2.
Impact of Subdoligranulum variabile supplementation on the prevention of diet-induced obesity in mice
Figure 3.
Figure 3.
Subdoligranulum variabile supplementation does not impact on glucose metabolism
Figure 4.
Figure 4.
Subdoligranulum variabile supplementation does not impact on lipid metabolism
Figure 5.
Figure 5.
Subdoligranulum variabile supplementation does not impact on short-chain fatty acids or gut barrier
See this image and copyright information in PMC

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Grants and funding

This work was supported by the Fonds de la Recherche Scientifique (FNRS FRFS-WELBIO) under the grants WELBIO-CR-2017C-02 and WELBIO-CR-2019C-02R. P.D.C. is a recipient of the Funds Baillet Latour (Grant for Medical Research 2015). Clinical investigation was supported by National Agency of Research (ANR “MicrObese”) and Programme Hospitalier de Recherche Clinique (PHRC, Microbaria), France.